Posttraumatic stress disorder (PTSD) occurs in some people after exposure to events that cause extreme fear or helplessness. The incidence of war zones worldwide and the prevalence of violence in large urban centers in the U.S. increases the likelihood of exposure to traumatizing events. Of those who survive such events, approximately 10% will develop this debilitating disorder that affects both the individual and their family. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a "one size fits all" treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorder or impede treatment. While both genes and environment interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. Moreover, amygdala projections modulate neuroendocrine systems, namely the hypothalamic-pituitary-adrenal (HPA) axis, which is the common pathway of the stress response. Cortisol performs important regulatory functions in these brain structures, and participates in the formation, processing, and retrieval of memories, particularly fearful ones. Furthermore, another neurobiological finding in PTSD is hyper-sensitive feedback of dexamethasone, a cortisol analogue, on the HPA axis. Although amygdala and cortisol feedback function have been studied separately in PTSD, the interaction of these two systems has not been studied in the same patients. The proposed study will provide innovative tools to tease apart the relationship between the amygdala and the HPA axis in a human clinical population. Our recent discovery of HPA axis suppression and fear dysregulation coupled with the development of new fear conditioning paradigms provides a unique opportunity to interrogate the amygdala-HPA interactions to determine aspects of the neurobiological underpinnings of the pathology related to PTSD. PUBLIC HEALTH RELEVANCE: Posttraumatic stress disorder (PTSD) is a highly debilitating and complex disorder frequently comorbid with many medical and psychiatric illnesses. Understanding the neurobiological mechanisms underlying this disorder will provide improved tools for targeting symptoms that are specific to PTSD. The ultimate goal of this proposal is to combine basic psychopathology research and basic neuroscience research to inform the development of novel and effective approaches for treating PTSD, particularly in high-risk populations such as low-income, African-Americans.